V

O-Dealkylation o-c2H5

O-Dealkylation

Parathion

Parathion

Desulfuration

Desulfuration

Norepinephrine

N-Dealkylation

Norepinephrine

Enterohepatic Cycle

Azathioprine

Nitrazepam

Azathioprine

Nitrazepam

Reduction

Benzpyrene Chlorpromazine

Reduction

Salicylic Acid Ionized
Oxidation

A. Examples of chemical reactions in drug biotransformation

Enterohepatic Cycle (A)

After an orally ingested drug has been absorbed from the gut, it is transported via the portal blood to the liver, where it can be conjugated to glucuronic or sul-furic acid (shown in B for salicylic acid and deacetylated bisacodyl, respectively) or to other organic acids. At the pH of body fluids, these acids are predominantly ionized; the negative charge confers high polarity upon the conjugated drug molecule and, hence, low membrane penetrability. The conjugated products may pass from hepatocyte into biliary fluid and from there back into the intestine. O-glucuronides can be cleaved by bacterial p-glucuronidases in the colon, enabling the liberated drug molecule to be reabsorbed. The enterohepatic cycle acts to trap drugs in the body. However, conjugated products enter not only the bile but also the blood. Glucuronides with a molecular weight (MW) > 300 preferentially pass into the blood, while those with MW > 300 enter the bile to a larger extent. Glucuronides circulating in the blood undergo glomerular filtration in the kidney and are excreted in urine because their decreased lipophilicity prevents tubular reabsorption.

Drugs that are subject to enterohe-patic cycling are, therefore, excreted slowly. Pertinent examples include digi-toxin and acidic nonsteroidal anti-inflammatory agents (p. 200).

Conjugations (B)

The most important of phase II conjugation reactions is glucuronidation. This reaction does not proceed spontaneously, but requires the activated form of glucuronic acid, namely glucuronic acid uridine diphosphate. Microsomal glucu-ronyl transferases link the activated glucuronic acid with an acceptor molecule. When the latter is a phenol or alcohol, an ether glucuronide will be formed. In the case of carboxyl-bearing molecules, an ester glucuronide is the result. All of these are O-glucuronides.

Amines may form N-glucuronides that, unlike O-glucuronides, are resistant to bacterial p-glucuronidases.

Soluble cytoplasmic sulfotrans-ferases conjugate activated sulfate (3'-phosphoadenine-5'-phosphosulfate) with alcohols and phenols. The conjugates are acids, as in the case of glucuro-nides. In this respect, they differ from conjugates formed by acetyltransfe-rases from activated acetate (acetyl-coenzyme A) and an alcohol or a phenol.

Acyltransferases are involved in the conjugation of the amino acids glycine or glutamine with carboxylic acids. In these cases, an amide bond is formed between the carboxyl groups of the acceptor and the amino group of the donor molecule (e.g., formation of salicyl-uric acid from salicylic acid and glycine). The acidic group of glycine or glutamine remains free.

Glucuro Conjugacion
Hydrophilic conjugation product

A. Enterohepatic cycle

UDP-a-Glucuronic acid

Glucuronyl-transferase

Salicylic acid

3'-Phosphoadenine-5'-phosphosulfate NH2

Emergency Panic Remedies

Emergency Panic Remedies

Eliminate Your Panic And Anxiety Attacks Instantly With These Proven Techniques! There’s
 very
 little
 in
 this 
world
 that 
is
 as 
frightening
 and
 uncomfortable
 as 
a panic
 attack. 

Once
 they
 start,
 panic
 attacks
 can
 send
 you
 spiraling
 out
 of control.

Get My Free Ebook


Post a comment